The present invention is directed to the treatment of rheumatoid arthritis (RA), and more particularly to a synthetic peptide sequence that has been discovered to induce pro-inflammatory effects in human synovial cells.
In the clotting of blood, a large protein dissolved in the plasma, known as “fibrinogen”, is cut-up by an enzyme into an insoluble protein known as “fibrin”, and other smaller fragments. Fibrin polymerizes to form the tough protein clot involved in blood coagulation. In addition to blood clots, polymerized fibrin is found in many inflamed, injured tissues, some of which are not the site of gross bleeding. Specifically, fibrin is found deposited on the inflamed joint surfaces of rheumatoid arthritis patients, in association with certain other inflammatory diseases, and with certain cancers. In rheumatoid arthritis, the amount of fibrin in the synovial membranes of the inflamed joints was found in the late 1970's to correlate with the severity of the disease, although the exact mechanism behind this relationship was not known.
Fibrin deposition, long recognized as a hallmark of acute and chronic inflammatory processes, has been localized within various inflamed tissues by histological, ultrastructural, and immunoflourescent procedures (References 1 and 2). A common theme of numerous studies is that fibrin plays an active role in the induction of inflammation (References 3-8), and demonstrate that fibrin can function beyond its classic role as a hemostatic plug or temporary matrix in response to injury. However, only recently has the direct impact of fibrin metabolism on the inflammatory process been seriously investigated, and specific roles assigned to fibrin or its products as mediators of the process (References 9-12). Although fibrin is abundantly present in many inflamed tissues rich in fibroblastic cells, no significant data on fibrin(ogen) metabolite induced gene expression by fibroblasts (FB) have been published.
Previously, research has focused on the cytokine pathways of adhesion molecule induction and adhesion molecule-related mechanisms thought to be important in connective tissue diseases, such as Rheumatoid Arthritis (RA) and Scleroderma (SD). In these diseases, evidence for altered fibrinolysis has been demonstrated, for example, in plasma and synovial fluids in RA (References 13-14). It has long been recognized that in most inflamed joints, the coagulation system is activated leading to the local generation of fibrin (Reference 15), and it has been hypothesized that the local fibrin deposition in arthritic joints could promote inflammation and destruction (Reference 16). Indeed, animal studies in which fibrin is implanted locally within joints induces a reaction that resembles human RA (Reference 28). Currently, studies are attempting to correlate associations between synovial fibrinolysis and levels of joint destruction in RA (Reference 17) and fibrinolysis with the severity of the disease state in SD (Reference 18), two diseases in which resident fibroblasts (FB) appear to play crucial roles. However, direct effects of fibrin on FB have not been previously examined with regard to the generation/maintenance of inflammation within connective tissue. Because of the universal nature of fibrin deposition in injured and inflamed tissue, determining the mediators, mechanisms and consequences of fibrin-induced activation of FB is important in not only understanding the pathways, but developing important new insights into the regulation of inflammation in connective tissue. Previous research pursued this avenue of investigation and it was found that fibrin clots could induce adhesion molecule expression in human synovial fibroblasts.
The treatment of RA has two clinical objectives: symptomatic reduction of pain and inflammation and prevention of joint damage. Scientists are experimenting with new drugs and biological agents that selectively block certain immune system activities associated with inflammation. Recent studies suggest that these represent promising approaches to treatment.
Current therapy for RA consists of non-steroidal anti-inflammatory drugs (NSAIDs), and as the disease progresses, oral steroids. Finally, disease modifying anti-rheumatic drugs (DMARDs) are added to the course of therapy.
It should be noted that no currently available agent truly improves the outcome of RA. DMARDs, such as methotrexate and sulfasalazine interfere with the inflammatory process but do not reverse or halt the progression of RA over long-term therapy. Moreover, while these agents initially work for most patients, both DMARDs and NSAIDs can cause serious side effects. And, while initial clinical response to DMARDs occurs in about 70-80% of patients, the effectiveness diminishes to approximately 20% of patients over time. It is estimated that 10% of the 2.5 million RA patients in the United States do not respond to current therapies.
Development of novel treatments for RA has been facilitated by two important factors: (1) progress in the understanding of the immunopathogenesis of RA, and (2) developments in biotechnology.